Role of PINK1 and parkin in the pathogenesis of Parkinson's disease
Final Report Abstract
The fellowship was aimed to gain a better understanding of the protein kinase PINK1. Mutations in PINK1 result in an autosomal recessive early-onset form of Parkinson’s disease. However, the exact role of PINK1 in the pathogenesis of this highly prevalent neurodegenerative disease is not clear yet. Recently, PINK1 and the E3 ubiquitin ligase Parkin have been suggested to regulate mitochondrial quality control: PINK1 accumulates on defective mitochondria, resulting in Parkin recruitment from the cytosol to the mitochondrial outer membrane, followed by the autophagic removal of these mitochondria, known as mitophagy. Two forms of PINK1 are usually detected on western blots: a full length form of about 62kDa and a cleaved form of about 53kDa. The precise subcellular and submitochondrial localization of PINK1, especially of the cleaved form, is highly controversial. During my fellowship, we have shown that both, the full length form as well as the cleaved form of PINK1, localize to the cytosolic phase of the mitochondrial outer membrane. Moreover, we found that the cleaved form is only loosely associated to the mitochondria and readily translocates to the cytosol. In addition, we have shown that contrary to full length PINK1, the cytosolic cleaved form of PINK1 actually attenuates mitophagy by physically binding Parkin and thus suppressing its mitochondrial translocation. This clarification of the subcellular and submitochondrial localization of the two major PINK1 forms and the discovery of their antagonistic functions, may lead to a better understanding of the PINK1 and Parkin mediated pathogenesis in Parkinson’s disease. Ultimately, these results could facilitate the identification of new therapeutic targets and thus could help improve patients’ outcomes in the future.
Publications
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Pink1 kinase and its membrane potential (Deltaψ)-dependent cleavage product both localize to outer mitochondrial membrane by unique targeting mode. J Biol Chem. 2012 Jun 29;287(27):22969-87
Becker D, Richter J, Tocilescu MA, Przedborski S, Voos W
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Submitochondrial localization of Pink1. Poster: 440.24/E20, Neuroscience 2012, New Orleans, LA, USA
Fedorowicz MA, Becker D, de Vries-Schneider RLA, Alessi DM, Guardia-Laguarta C, Liu Y, May J, Voos W, Przedborski S
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Cytosolic cleaved PINK1 represses Parkin translocation to mitochondria and mitophagy. EMBO Rep. 2014 Jan;15(1):86-93
Fedorowicz MA, de Vries-Schneider RL, Rüb C, Becker D, Huang Y, Zhou C, Alessi Wolken DM, Voos W, Liu Y, Przedborski S
